Methods and compositions for regulating memory consolidation

Abstract

The present invention is based on the discovery of genes that are up- or down-regulated in inhibitory avoidance, e.g., long-term memory, which genes are therefor believed to have roles in memory consolidation. In particular, we have discovered that memory consolidation involves the regulation of expression of such genes as zif268 (EGR1), insulin-like growth factor (IGF-1), glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), c/EBPβ and VGF. For ease of reading, these genes are collectively referred to herein as “LTM genes”, and their encoded proteins as “LTM proteins”.

We claim:  
     
         1 . A method for modulating long term memory consolidation in an animal comprising treating an animal with an agent that modulates the activity of one or more of zif268, insulin-like growth factor, glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), c/EBPβ and VGF.  
     
     
         2 . A method for enhancing long term memory consolidation in an animal comprising treating an animal with an agent that modulates a signal transduction pathway of glutamate receptor 1 (GluR1) or glutamate receptor 2 (GluR2), which agent is a ligand for the GluR1 or GluR2 receptor.  
     
     
         3 . A method for identifying an agent which modulates memory consolidation, comprising, 
 (i) providing a reaction system for detecting the activity of a product encoded by a gene selected from the group consisting of of zif268, insulin-like growth factor, glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), c/EBPβ and VGF;    (ii) contacting said system with a test compound; and    (iii) determining if the test compound alters the activity of the gene product.    
     
     
         4 . A method for identifying an agent which modulates memory consolidation, comprising, 
 (i) providing a reaction system for detecting the level of expression of a gene selected from the group consisting of of zif 268, insulin-like growth factor, glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), c/EBPβ and VGF;    (ii) contacting said system with a test compound; and    (iii) determining if the test compound alters the level of expression of the gene.    
     
     
         5 . The method of  claim 3  or  4 , wherein the reaction system is a cell-free system.  
     
     
         6 . The method of  claim 5 , wherein the cell-free system is purified protein preparation.  
     
     
         7 . The method of  claim 5 , wherein the cell-free system is a cell-lysate.  
     
     
         8 . The method of  claim 3  or  4 , wherein the reaction system is a whole cell system.  
     
     
         9 . The method of  claim 3  or  4 , wherein the test agent is a organic molecule having a molecular weight less than 2500 amu.  
     
     
         10 . The method of  claim 3  or  4 , which is repeated for a plurality of different test agents.  
     
     
         11 . A pharmaceutical preparation comprising, one or more compounds identified in the assay of  claim 3  or  4 , formulated in a pharmaceutically acceptable excipient.  
     
     
         12 . The pharmaceutical preparation of  claim 11 , further including one or more of a neuronal growth factor, a neuronal survival factor, and a neuronal tropic factor.  
     
     
         13 . The pharmaceutical preparation of  claim 11 , further including an agent that activates CREB-dependent transcription in an amount sufficient to produce a memory enhancing effect.  
     
     
         14 . A method for enhancing memory consolidation in an animal, or otherwise enhancing the functional performance of CNS neurons, comprising administering to an animal a pharmaceutical preparation of  claim 11 .  
     
     
         15 . A method for augmenting learning and memory, or otherwise enhancing the functional performance of CNS neurons, comprising administering to an animal a pharmaceutical preparation of  claim 11 .  
     
     
         16 . The method of  claim 14  or  15 , further comprising administering, conjointly with the pharmaceutical preparation, one or more of a neuronal growth factor, a neuronal survival factor, and a neuronal tropic factor.  
     
     
         17 . The method of  claim 14  or  15 , further comprising administering, conjointly with the pharmaceutical preparation, an agent that activates CREB-dependent transcription in an amount sufficient to produce a memory enhancing effect.  
     
     
         18 . The method of  claim 17 , wherein the CREB activating agent is a cAMP elevating agent.  
     
     
         19 . The method of  claim 18 , wherein at least one cAMP agonist activates adenylate cyclase.  
     
     
         20 . The method of  claim 17 , wherein the CREB activating agent is a cAMP analog.  
     
     
         21 . The method of  claim 17 , wherein the CREB activating agent is a cAMP phosphodiesterase inhibitor.  
     
     
         22 . A method for assessing a patient for learning and/or memory functional performance including a step of detecting the expression of a gene selected from the group consisting of of zif 268, insulin-like growth factor, glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), c/EBPβ and VGF, or the level of activity of a gene product thereof, in the patient's hippocampus.  
     
     
         23 . A method for assessing a patient for learning and/or memory functional performance including a step of detecting the expression of, or a mutation in, one or more genes selected from the group consisting of zif 268, insulin-like growth factor, glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), c/EBPβ and VGF, or the level of activity of the gene products thereof, (optionally) in the patient's hippocampus.  
     
     
         24 . A method of conducting a drug discovery business comprising: 
 (i) identifying, by the assay of  claim 3  or  4 , a test compound which the level of expression of the gene or the activity of the gene product;    (ii) conducting therapeutic profiling of agents identified in step (i), or further analogs thereof, for efficacy and toxicity in animals; and    (iii) formulating a pharmaceutical preparation including one or more agents identified in step (ii) as having an acceptable therapeutic profile.    
     
     
         25 . The method of  claim 24 , including an additional step of establishing a distribution system for distributing the pharmaceutical preparation for sale, and may optionally include establishing a sales group for marketing the pharmaceutical preparation.  
     
     
         26 . A method of conducting a target discovery business comprising: 
 (i) identifying, by the assay of  claim 3  or  4 , a test compound which the level of expression of the gene or the activity of the gene product;    (ii) (optionally) conducting therapeutic profiling of agents identified in step (i), or further analogs thereof, for efficacy and toxicity in animals; and    (iii). licensing, to a third party, the rights for further drug development of said identified agents.